Role of Rho-kinase and its inhibitors in pulmonary hypertension

Pharmacology and Therapeutics

Volumn 137, Issue 3, 2013, Pages 352-364

  Duong Quy, Sy ^a   Bei, Yihua ^a,b   Liu, Zhongmin ^b   Dinh Xuan, Anh Tuan ^a,b  

^a Université Paris Descartes ^*  (France)

^b TONGJI UNIVERSITY SCHOOL OF MEDICINE   (China)

Author keywords

Keywords; Pulmonary hypertension; Rho kinase; RhoA

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; ACTIVIN RECEPTOR LIKE KINASE 1; BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CHEMOKINE RECEPTOR CX3CR1; ENDOGLIN; ENDOTHELIAL NITRIC OXIDE SYNTHASE; FASUDIL; FRACTALKINE; GUANOSINE TRIPHOSPHATASE; INTERLEUKIN 1BETA; INTERLEUKIN 6; RHO KINASE; RHO KINASE INHIBITOR; TOCILIZUMAB;

CELL PROLIFERATION; CHEMICAL STRUCTURE; CONGENITAL HEART DISEASE; CYTOKINE RELEASE; DISEASE CLASSIFICATION; DNA POLYMORPHISM; DRUG EFFICACY; DRUG METABOLISM; GENE MUTATION; GENETIC DISORDER; GENETIC PREDISPOSITION; HEART LEFT RIGHT SHUNT; HEART RIGHT VENTRICLE HYPERTROPHY; HUMAN; INFLAMMATION; LUNG VASCULAR RESISTANCE; LUNG VASOCONSTRICTION; NONHUMAN; PATHOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PULMONARY HYPERTENSION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; VASCULAR SMOOTH MUSCLE; VASODILATATION;

ANIMALS; HUMANS; HYPERTENSION, PULMONARY; MUSCLE, SMOOTH, VASCULAR; PROTEIN KINASE INHIBITORS; RHO-ASSOCIATED KINASES;

EID: 84874113901     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2012.12.003     Document Type: Review

References (177)

1. K. Abe, H. Shimokawa, K. Morikawa, T. Uwatoku, K. Oi, and Matsumoto Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats Circ Res 94 2004 385 393
2. K. Abe, S. Tawara, K. Oi, T. Hizume, T. Uwatoku, and Y. Fukumoto Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice J Cardiovasc Pharmacol 48 2006 280 285
3. A.S. Alberts, N. Bouquin, L.H. Johnston, and R. Treisman Analysis of RhoA-binding proteins reveals an interaction domain conserved in heterotrimeric G protein beta subunits and the yeast response regulator protein Skn7 J Biol Chem 273 1998 8616 8622
4. M. Amano, K. Chihara, N. Nakamura, T. Kaneko, Y. Matsuura, and K. Kaibuchi The COOH terminus of Rho-kinase negatively regulates rho-kinase activity J Biol Chem 274 1999 32418 32424
5. M. Amano, Y. Fukata, and K. Kaibuchi Regulation and functions of Rho-associated kinase Exp Cell Res 261 2000 44 51
6. R.K. Assoian, and E.E. Marcantonio The extracellular matrix as a cell cycle control element in atherosclerosis and restenosis J Clin Invest 98 1996 2436 2439
7. S. Aznar, and J.C. Lacal Rho signals to cell growth and apoptosis Cancer Lett 165 2001 1 10
8. K. Balabanian, A. Foussat, P. Dorfmüller, I. Durand-Gasselin, F. Capel, and L. Bouchet-Delbos CX(3)C chemokine fractalkine in pulmonary arterial hypertension Am J Respir Crit Care Med 165 2002 1419 1425
9. S.A. Barman Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C Am J Physiol Lung Cell Mol Physiol 293 2007 L472 L479
10. T.J. Batchelor, J.R. Sadaba, A. Ishola, P. Pacaud, C.M. Munsch, and D.J. Beech Rho-kinase inhibitors prevent agonist-induced vasospasm in human internal mammary artery Br J Pharmacol 132 2001 302 308
11. N. Begum, O.A. Sandu, and N. Duddy Negative regulation of rho signaling by insulin and its impact on actin cytoskeleton organization in vascular smooth muscle cells: Role of nitric oxide and cyclic guanosine monophosphate signaling pathways Diabetes 51 2002 2256 2263
12. P.J. Bilan, J.S. Moyers, and C.R. Kahn The ras-related protein rad associates with the cytoskeleton in a non-lipid-dependent manner Exp Cell Res 242 1998 391 400
13. R.N. Channick, G. Simonneau, O. Sitbon, I.M. Robbins, A. Frost, and V.F. Tapson Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study Lancet 358 2001 1119 1123
14. V. Chevrier, M. Piel, N. Collomb, Y. Saoudi, R. Frank, and M. Paintrand The Rho-associated protein kinase p160ROCK is required for centrosome positioning J Cell Biol 157 2002 807 817
15. K. Chitaley, and R.C. Webb Nitric oxide induces dilation of rat aorta via inhibition of rho-kinase signaling Hypertension 39 2002 438 442
16. B.W. Christman, C.D. McPherson, J.H. Newman, G.A. King, G.R. Bernard, and B.M. Groves An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension N Engl J Med 327 1992 70 75
17. G.E. D'Alonzo, R.J. Barst, S.M. Ayres, E.H. Bergofsky, B.H. Brundage, and K.M. Detre Survival in patients with primary pulmonary hypertension. Results from a national prospective registry Ann Intern Med 115 1991 343 349
18. B.K. Dahal, D. Kosanovic, P.K. Pamarthi, A. Sydykov, Y.-J. Lai, and R. Kast Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension Eur Respir J 36 2010 808 818
19. Z.-K. Dai, B.-N. Wu, I.-C. Chen, C.-Y. Chai, J.-R. Wu, and S.-H. Chou Attenuation of pulmonary hypertension secondary to left ventricular dysfunction in the rat by Rho-kinase inhibitor fasudil Pediatr Pulmonol 46 2011 45 59
20. S.P. Davies, H. Reddy, M. Caivano, and P. Cohen Specificity and mechanism of action of some commonly used protein kinase inhibitors Biochem J 351 2000 95 105
21. N. Desbuards, D. Antier, G.Y. Rochefort, C.S. Apfeldorfer, E. Schenck, and G. Hanton Dexfenfluramine discontinuous treatment does not worsen hypoxia-induced pulmonary vascular remodeling but activates RhoA/ROCK pathway: Consequences on pulmonary hypertension Eur J Pharmacol 602 2009 355 363
22. K.P. Dingemans, and C.A. Wagenvoort Pulmonary arteries and veins in experimental hypoxia. An ultrastructural study Am J Pathol 93 1978 353 368
23. e Z. Do, Y. Fukumoto, A. Takaki, S. Tawara, J. Ohashi, and M. Nakano Evidence for Rho-kinase activation in patients with pulmonary arterial hypertension Circ J 73 2009 1731 1739
24. J.D. Doran, X. Liu, P. Taslimi, A. Saadat, and T. Fox New insights into the structure-function relationships of Rho-associated kinase: A thermodynamic and hydrodynamic study of the dimer-to-monomer transition and its kinetic implications Biochem J 384 2004 255 262
25. P. Dorfmüller, F. Perros, K. Balabanian, and M. Humbert Inflammation in pulmonary arterial hypertension Eur Respir J 22 2003 358 363
26. S. Eddahibi, A. Chaouat, N. Morrell, E. Fadel, C. Fuhrman, and A.-S. Bugnet Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease Circulation 108 2003 1839 1844
27. S. Eddahibi, M. Humbert, E. Fadel, B. Raffestin, M. Darmon, and F. Capron Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension J Clin Invest 108 2001 1141 1150
28. M. Emerson, S. Momi, W. Paul, P.F. Alberti, C. Page, and P. Gresele Endogenous nitric oxide acts as a natural antithrombotic agent in vivo by inhibiting platelet aggregation in the pulmonary vasculature Thromb Haemost 81 1999 961 966
29. M. Eto, S. Senba, F. Morita, and M. Yazawa Molecular cloning of a novel phosphorylation-dependent inhibitory protein of protein phosphatase-1 (CPI17) in smooth muscle: Its specific localization in smooth muscle FEBS Lett 410 1997 356 360
30. K.A. Fagan, B.W. Fouty, R.C. Tyler, K.G. Morris Jr., L.K. Hepler, and K. Sato The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia J Clin Invest 103 1999 291 299
31. K.A. Fagan, M. Oka, N.R. Bauer, S.A. Gebb, D.D. Ivy, and K.G. Morris Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase Am J Physiol Lung Cell Mol Physiol 287 2004 L656 L664
32. J. Feng, M. Ito, K. Ichikawa, N. Isaka, M. Nishikawa, and D.J. Hartshorne Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase J Biol Chem 274 1999 37385 37390
33. J. Feng, M. Ito, Y. Kureishi, K. Ichikawa, M. Amano, and N. Isaka Rho-associated kinase of chicken gizzard smooth muscle J Biol Chem 274 1999 3744 3752
34. V.C. Foletta, M.A. Lim, J. Soosairajah, A.P. Kelly, E.G. Stanley, and M. Shannon Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1 J Cell Biol 162 2003 1089 1098
35. K. Fujisawa, P. Madaule, T. Ishizaki, G. Watanabe, H. Bito, and Y. Saito Different regions of Rho determine Rho-selective binding of different classes of Rho target molecules J Biol Chem 273 1998 18943 18949
36. H. Fujita, Y. Fukumoto, K. Saji, K. Sugimura, J. Demachi, and J. Nawata Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension Heart Vessels 25 2010 144 149
37. Y. Fukata, M. Amano, and K. Kaibuchi Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells Trends Pharmacol Sci 22 2001 32 39
38. Y. Fukumoto, T. Matoba, A. Ito, H. Tanaka, T. Kishi, and S. Hayashidani Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension Heart 91 2005 391 392
39. Y. Furuya, T. Satoh, and M. Kuwana Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension Int J Rheumatol 2010 2010 720305
40. N. Galiè, M.M. Hoeper, M. Humbert, A. Torbicki, J.-L. Vachiery, and J.A. Barbera Guidelines for the diagnosis and treatment of pulmonary hypertension Eur Respir J 34 2009 1219 1263
41. N. Galié, A. Manes, and A. Branzi The endothelin system in pulmonary arterial hypertension Cardiovasc Res 61 2004 227 237
42. A. Giaid, and D. Saleh Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension N Engl J Med 333 1995 214 221
43. J. Gien, G.J. Seedorf, V. Balasubramaniam, N. Tseng, N. Markham, and S.H. Abman Chronic intrauterine pulmonary hypertension increases endothelial cell Rho kinase activity and impairs angiogenesis in vitro Am J Physiol Lung Cell Mol Physiol 295 2008 L680 L687
44. R.E. Girgis, D. Li, X. Zhan, J.G.N. Garcia, R.M. Tuder, and P.M. Hassoun Attenuation of chronic hypoxic pulmonary hypertension by simvastatin Am J Physiol Heart Circ Physiol 285 2003 H938 H945
45. R.E. Girgis, S. Mozammel, H.C. Champion, D. Li, X. Peng, and L. Shimoda Regression of chronic hypoxic pulmonary hypertension by simvastatin Am J Physiol Lung Cell Mol Physiol 292 2007 L1105 L1110
46. C. Guilluy, S. Eddahibi, C. Agard, C. Guignabert, M. Izikki, and L. Tu RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling Am J Respir Crit Care Med 179 2009 1151 1158
47. C. Guilluy, V. Sauzeau, M. Rolli-Derkinderen, P. Guérin, C. Sagan, and P. Pacaud Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension Br J Pharmacol 146 2005 1010 1018
48. P.M. Hassoun, L. Mouthon, J.A. Barberà, S. Eddahibi, S.C. Flores, and F. Grimminger Inflammation, growth factors, and pulmonary vascular remodeling J Am Coll Cardiol 54 1 Suppl. 2009 S10 S19
49. S. Hatano, and T. Strasser Primary pulmonary hypertension Report on a WHO Meeting. October 15-17, 1973 1975 World Health Organization Geneva 1 45
50. A.R. Hemnes, A. Zaiman, and H.C. Champion PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation Am J Physiol Lung Cell Mol Physiol 294 2008 L24 L33
51. D.T. Hess, A. Matsumoto, R. Nudelman, and J.S. Stamler S-nitrosylation: spectrum and specificity Nat Cell Biol 3 2001 E46 E49
52. T.W. Higenbottam, and E.A. Laude Endothelial dysfunction providing the basis for the treatment of pulmonary hypertension: Giles F. Filley lecture Chest 114 1 Suppl. 1998 72S 79S
53. M.M. Hoeper, and A.T. Dinh-Xuan Combination therapy for pulmonary arterial hypertension: still more questions than answers Eur Respir J 24 2004 339 340
54. N. Homma, T. Nagaoka, V. Karoor, M. Imamura, L. Taraseviciene-Stewart, and L.A. Walker Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone Am J Physiol Lung Cell Mol Physiol 295 2008 L71 L78
55. N. Homma, T. Nagaoka, Y. Morio, H. Ota, S.A. Gebb, and V. Karoor Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation J Cardiovasc Pharmacol 50 2007 697 702
56. M. Humbert, G. Monti, F. Brenot, O. Sitbon, A. Portier, and L. Grangeot-Keros Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension Am J Respir Crit Care Med 151 1995 1628 1631
57. M. Humbert, N.W. Morrell, S.L. Archer, K.R. Stenmark, M.R. MacLean, and I.M. Lang Cellular and molecular pathobiology of pulmonary arterial hypertension J Am Coll Cardiol 43 12 Suppl. S 2004 13S 24S
58. R.A. Isern, M. Yaneva, E. Weiner, A. Parke, N. Rothfield, and D. Dantzker Autoantibodies in patients with primary pulmonary hypertension: association with anti-Ku Am J Med 93 1992 307 312
59. K. Ishikura, N. Yamada, M. Ito, S. Ota, M. Nakamura, and N. Isaka Beneficial acute effects of rho-kinase inhibitor in patients with pulmonary arterial hypertension Circ J 70 2006 174 178
60. T. Ishizaki, M. Maekawa, K. Fujisawa, K. Okawa, A. Iwamatsu, and A. Fujita The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase EMBO J 15 1996 1885 1893
61. T. Ishizaki, M. Uehata, I. Tamechika, J. Keel, K. Nonomura, and M. Maekawa Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases Mol Pharmacol 57 2000 976 983
62. K. Ito, T. Ichiki, K. Ohi, K. Egashira, M. Ohta, and K. Taguchi Pulmonary capillary hemangiomatosis with severe pulmonary hypertension Circ J 67 2003 793 795
63. J.F. Jasmin, M. Lucas, P. Cernacek, and J. Dupuis Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension Circulation 103 2001 314 318
64. T.K. Jeffery, and J.C. Wanstall Pulmonary vascular remodeling: A target for therapeutic intervention in pulmonary hypertension Pharmacol Ther 92 2001 1 20
65. B.H. Jiang, S. Tawara, K. Abe, A. Takaki, Y. Fukumoto, and H. Shimokawa Acute vasodilator effect of fasudil, a Rho-kinase inhibitor, in monocrotaline-induced pulmonary hypertension in rats J Cardiovasc Pharmacol 49 2007 85 89
66. R. Jones, M. Jacobson, and W. Steudel alpha-smooth-muscle actin and microvascular precursor smooth-muscle cells in pulmonary hypertension Am J Respir Cell Mol Biol 20 1999 582 594
67. M. Kamiyama, K. Utsunomiya, K. Taniguchi, T. Yokota, H. Kurata, and N. Tajima Contribution of Rho A and Rho kinase to platelet-derived growth factor-BB-induced proliferation of vascular smooth muscle cells J Atheroscler Thromb 10 2003 117 123
68. T. Kanda, K. Hayashi, S. Wakino, K. Homma, K. Yoshioka, and K. Hasegawa Role of Rho-kinase and p27 in angiotensin II-induced vascular injury Hypertension 45 2005 724 729
69. S. Kawabata, J. Usukura, N. Morone, M. Ito, A. Iwamatsu, and K. Kaibuchi Interaction of Rho-kinase with myosin II at stress fibres Genes Cells 9 2004 653 660
70. A. Keil, I.E. Blom, R. Goldschmeding, and H.D. Rupprecht Nitric oxide down-regulates connective tissue growth factor in rat mesangial cells Kidney Int 62 2002 401 411
71. I. Khan, M.A. Oriowo, B. Chandrasekhar, and E.A. Kadavil Attenuated noradrenaline-induced contraction of pulmonary arteries from rats treated with monocrotaline: Role of rho kinase J Vasc Res 42 2005 433 440
72. G.A. Knock, V.A. Snetkov, Y. Shaifta, M. Connolly, S. Drndarski, and A. Noah Superoxide constricts rat pulmonary arteries via Rho-kinase-mediated Ca(2+) sensitization Free Radic Biol Med 46 2009 633 642
73. M. Koyama, M. Ito, J. Feng, T. Seko, K. Shiraki, and K. Takase Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase FEBS Lett 475 2000 197 200
74. J.C. Krepinsky, A.J. Ingram, D. Tang, D. Wu, L. Liu, and J.W. Scholey Nitric oxide inhibits stretch-induced MAPK activation in mesangial cells through RhoA inactivation J Am Soc Nephrol 14 2003 2790 2800
75. K.B. Lane, R.D. Machado, M.W. Pauciulo, J.R. Thomson, J.A. Phillips III, and J.E. Loyd Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension Nat Genet 26 2000 81 84
76. U. Laufs, M. Endres, and J.K. Liao Regulation of endothelial NO production by Rho GTPase Med Klin (Munich) 94 1999 211 218
77. U. Laufs, and J.K. Liao Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase J Biol Chem 273 1998 24266 24271
78. U. Laufs, D. Marra, K. Node, and J.K. Liao 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1) J Biol Chem 274 1999 21926 21931
79. T. Leung, X.Q. Chen, E. Manser, and L. Lim The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton Mol Cell Biol 16 1996 5313 5327
80. T. Leung, E. Manser, L. Tan, and L. Lim A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes J Biol Chem 270 1995 29051 29054
81. X.H. Li, J. Peng, N. Tan, W.H. Wu, T.T. Li, and R.Z. Shi Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension Vascul Pharmacol 53 2010 223 229
82. F. Li, W. Xia, A. Li, C. Zhao, and R. Sun Long-term inhibition of Rho kinase with fasudil attenuates high flow induced pulmonary artery remodeling in rats Pharmacol Res 55 2007 64 71
83. F. Li, W. Xia, S. Yuan, and R. Sun Acute inhibition of Rho-kinase attenuates pulmonary hypertension in patients with congenital heart disease Pediatr Cardiol 30 2009 363 366
84. J.K. Liao, and U. Laufs Pleiotropic effects of statins Annu Rev Pharmacol Toxicol 45 2005 89 118
85. G. Loirand, P. Guérin, and P. Pacaud Rho kinases in cardiovascular physiology and pathophysiology Circ Res 98 2006 322 334
86. R.D. Machado, M.A. Aldred, V. James, R.E. Harrison, B. Patel, and E.C. Schwalbe Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension Hum Mutat 27 2006 121 132
87. R.D. Machado, O. Eickelberg, C.G. Elliott, M.W. Geraci, M. Hanaoka, and J.E. Loyd Genetics and genomics of pulmonary arterial hypertension J Am Coll Cardiol 54 1 Suppl. 2009 S32 S42
88. S. Mahapatra, R.A. Nishimura, J.K. Oh, and M.D. McGoon The prognostic value of pulmonary vascular capacitance determined by Doppler echocardiography in patients with pulmonary arterial hypertension J Am Soc Echocardiogr 19 2006 1045 1050
89. S. Mahapatra, R.A. Nishimura, P. Sorajja, S. Cha, and M.D. McGoon Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension J Am Coll Cardiol 47 2006 799 803
90. T. Matsui, M. Amano, T. Yamamoto, K. Chihara, M. Nakafuku, and M. Ito Rho-associated kinase, a novel serine/threonine kinase, as a putative target for small GTP binding protein Rho EMBO J 15 1996 2208 2216
91. P.J. McNamara, P. Murthy, C. Kantores, L. Teixeira, D. Engelberts, and T. van Vliet Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide Am J Physiol Lung Cell Mol Physiol 294 2008 L205 L213
92. S. Moncada, R.M. Palmer, and E.A. Higgs Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication Biochem Pharmacol 38 1989 1709 1715
93. D. Montani, L.C. Price, P. Dorfmuller, L. Achouh, X. Jaïs, and A. Yaïci Pulmonary veno-occlusive disease Eur Respir J 33 2009 189 200
94. S. Moosmang, V. Schulla, A. Welling, R. Feil, S. Feil, and J.W. Wegener Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation EMBO J 22 2003 6027 6034
95. D.O. Morgan Principles of CDK regulation Nature 374 1995 131 134
96. N.W. Morrell, S. Adnot, S.L. Archer, J. Dupuis, P.L. Jones, and M.R. MacLean Cellular and molecular basis of pulmonary arterial hypertension J Am Coll Cardiol 54 1 Suppl. 2009 S20 S31
97. K.T.B. Mouchaers, I. Schalij, M.A. de Boer, P.E. Postmus, V.W.M. van Hinsbergh, and G.P. van Nieuw Amerongen Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: Comparison with bosentan and sildenafil Eur Respir J 36 2010 800 807
98. R. Naeije, and S. Huez Expert opinion on available options treating pulmonary arterial hypertension Expert Opin Pharmacother 8 2007 2247 2265
99. T. Nagaoka, K.A. Fagan, S.A. Gebb, K.G. Morris, T. Suzuki, and H. Shimokawa Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension Am J Respir Crit Care Med 171 2005 494 499
100. T. Nagaoka, S.A. Gebb, V. Karoor, N. Homma, K.G. Morris, and I.F. McMurtry Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat J Appl Physiol 100 2006 996 1002
101. T. Nagaoka, Y. Morio, N. Casanova, N. Bauer, S. Gebb, and I. McMurtry Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats Am J Physiol Lung Cell Mol Physiol 287 2004 L665 L672
102. O. Nakagawa, K. Fujisawa, T. Ishizaki, Y. Saito, K. Nakao, and S. Narumiya ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice FEBS Lett 392 1996 189 193
103. J.H. Newman, R.C. Trembath, J.A. Morse, E. Grunig, J.E. Loyd, and S. Adnot Genetic basis of pulmonary arterial hypertension: current understanding and future directions J Am Coll Cardiol 43 12 Suppl. S 2004 33S 39S
104. J.H. Newman, L. Wheeler, K.B. Lane, E. Loyd, R. Gaddipati, and J.A. Phillips III Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred N Engl J Med 345 2001 319 324
105. W. Ni, K. Egashira, C. Kataoka, S. Kitamoto, M. Koyanagi, and S. Inoue Antiinflammatory and antiarteriosclerotic actions of HMG-CoA reductase inhibitors in a rat model of chronic inhibition of nitric oxide synthesis Circ Res 89 2001 415 421
106. T. Nishimura, L.T. Vaszar, J.L. Faul, G. Zhao, G.J. Berry, and L. Shi Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells Circulation 108 2003 1640 1645
107. M. Oka, N. Homma, L. Taraseviciene-Stewart, K.G. Morris, D. Kraskauskas, and N. Burns Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats Circ Res 100 2007 923 929
108. H. Olschewski, G. Simonneau, N. Galiè, T. Higenbottam, R. Naeije, and L.J. Rubin Inhaled iloprost for severe pulmonary hypertension N Engl J Med 347 2002 322 329
109. H.I. Palevsky, B.L. Schloo, G.G. Pietra, K.T. Weber, J.S. Janicki, and E. Rubin Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents Circulation 80 1989 1207 1221
110. F. Perros, P. Dorfmüller, R. Souza, I. Durand-Gasselin, V. Godot, and F. Capel Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension Eur Respir J 29 2007 937 943
111. F. Perros, P. Dorfmüller, R. Souza, I. Durand-Gasselin, S. Mussot, and M. Mazmanian Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension Eur Respir J 29 2007 462 468
112. E. Piddini, J.A. Schmid, R. de Martin, and C.G. Dotti The Ras-like GTPase Gem is involved in cell shape remodelling and interacts with the novel kinesin-like protein KIF9 EMBO J 20 2001 4076 4087
113. D.J. Pierson Pathophysiology and clinical effects of chronic hypoxia Respir Care 45 2000 39 51 (discussion 51-53)
114. G.G. Pietra, F. Capron, S. Stewart, O. Leone, M. Humbert, and I.M. Robbins Pathologic assessment of vasculopathies in pulmonary hypertension J Am Coll Cardiol 43 12 Suppl. S 2004 25S 32S
115. M. Rabinovitch, W. Gamble, A.S. Nadas, O.S. Miettinen, and L. Reid Rat pulmonary circulation after chronic hypoxia: Hemodynamic and structural features Am J Physiol 236 1979 H818 H827
116. K. Riento, R.M. Guasch, R. Garg, B. Jin, and A.J. Ridley RhoE binds to ROCK I and inhibits downstream signaling Mol Cell Biol 23 2003 4219 4229
117. K. Riento, and A.J. Ridley Rocks: multifunctional kinases in cell behaviour Nat Rev Mol Cell Biol 4 2003 446 456
118. Y. Rikitake, H.-H. Kim, Z. Huang, M. Seto, K. Yano, and T. Asano Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection Stroke 36 2005 2251 2257
119. Y. Rikitake, and J.K. Liao Rho GTPases, statins, and nitric oxide Circ Res 97 2005 1232 1235
120. L.J. Rubin, D.B. Badesch, R.J. Barst, N. Galie, C.M. Black, and A. Keogh Bosentan therapy for pulmonary arterial hypertension N Engl J Med 346 2002 896 903
121. S. Sakao, L. Taraseviciene-Stewart, C.D. Cool, Y. Tada, Y. Kasahara, and K. Kurosu VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells FASEB J 21 2007 3640 3652
122. S. Sakurada, H. Okamoto, N. Takuwa, N. Sugimoto, and Y. Takuwa Rho activation in excitatory agonist-stimulated vascular smooth muscle Am J Physiol Cell Physiol 281 2001 C571 C578
123. O. Sanchez, E. Marcos, F. Perros, E. Fadel, L. Tu, and M. Humbert Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension Am J Respir Crit Care Med 176 2007 1041 1047
124. B.K.S. Sastry, C. Narasimhan, N.K. Reddy, and B.S. Raju Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo-controlled, double-blind, crossover study J Am Coll Cardiol 43 2004 1149 1153
125. M. Sata Role of circulating vascular progenitors in angiogenesis, vascular healing, and pulmonary hypertension: Lessons from animal models Arterioscler Thromb Vasc Biol 26 2006 1008 1014
126. S. Satoh, T. Utsunomiya, K. Tsurui, T. Kobayashi, I. Ikegaki, and Y. Sasaki Pharmacological profile of hydroxy fasudil as a selective rho kinase inhibitor on ischemic brain damage Life Sci 69 2001 1441 1453
127. V. Sauzeau, H. Le Jeune, C. Cario-Toumaniantz, A. Smolenski, S.M. Lohmann, and J. Bertoglio Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle J Biol Chem 275 2000 21722 21729
128. V. Sauzeau, E. Le Mellionnec, J. Bertoglio, E. Scalbert, P. Pacaud, and G. Loirand Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase Circ Res 88 2001 1102 1104
129. N. Sawada, H. Itoh, K. Ueyama, J. Yamashita, K. Doi, and T.H. Chun Inhibition of rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries Circulation 101 2000 2030 2033
130. T.M. Seasholtz, M. Majumdar, D.D. Kaplan, and J.H. Brown Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and migration Circ Res 84 1999 1186 1193
131. M. Sebbagh, J. Hamelin, J. Bertoglio, E. Solary, and J. Bréard Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner J Exp Med 201 2005 465 471
132. M. Sebbagh, C. Renvoizé, J. Hamelin, N. Riché, J. Bertoglio, and J. Bréard Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing Nat Cell Biol 3 2001 346 352
133. C.J. Sherr, and J.M. Roberts Inhibitors of mammalian G1 cyclin-dependent kinases Genes Dev 9 1995 1149 1163
134. H. Shimokawa Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases J Cardiovasc Pharmacol 39 2002 319 327
135. H. Shimokawa, K. Hiramori, H. Iinuma, S. Hosoda, H. Kishida, and H. Osada Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: A multicenter study J Cardiovasc Pharmacol 40 2002 751 761
136. H. Shimokawa, M. Seto, N. Katsumata, M. Amano, T. Kozai, and T. Yamawaki Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm Cardiovasc Res 43 1999 1029 1039
137. S. Shirao, S. Kashiwagi, M. Sato, S. Miwa, F. Nakao, and T. Kurokawa Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca2+ sensitization in the bovine cerebral artery: unimportant role for protein kinase C Circ Res 91 2002 112 119
138. G. Simonneau, N. Galiè, L.J. Rubin, D. Langleben, W. Seeger, and G. Domenighetti Clinical classification of pulmonary hypertension J Am Coll Cardiol 43 12 Suppl. S 2004 5S 12S
139. W.C. Sin, X.Q. Chen, T. Leung, and L. Lim RhoA-binding kinase alpha translocation is facilitated by the collapse of the vimentin intermediate filament network Mol Cell Biol 18 1998 6325 6339
140. O. Sitbon, M. Humbert, H. Nunes, F. Parent, G. Garcia, and P. Hervé Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival J Am Coll Cardiol 40 2002 780 788
141. A.P. Somlyo, and A.V. Somlyo Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: Modulated by G proteins, kinases, and myosin phosphatase Physiol Rev 83 2003 1325 1358
142. N. Sommer, A. Dietrich, R.T. Schermuly, H.A. Ghofrani, T. Gudermann, and R. Schulz Regulation of hypoxic pulmonary vasoconstriction: Basic mechanisms Eur Respir J 32 2008 1639 1651
143. J.S. Stamler, S. Lamas, and F.C. Fang Nitrosylation. The prototypic redox-based signaling mechanism Cell 106 2001 675 683
144. M.K. Steiner, O.L. Syrkina, N. Kolliputi, E.J. Mark, C.A. Hales, and A.B. Waxman Interleukin-6 overexpression induces pulmonary hypertension Circ Res 104 2009 236 244 (28 pp. following 244)
145. B. Sztrymf, F. Coulet, B. Girerd, A. Yaici, X. Jais, and O. Sitbon Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation Am J Respir Crit Care Med 177 2008 1377 1383
146. N. Takahashi, H. Tuiki, H. Saya, and K. Kaibuchi Localization of the gene coding for ROCK II/Rho kinase on human chromosome 2p24 Genomics 55 1999 235 237
147. M. Takemoto, J. Sun, J. Hiroki, H. Shimokawa, and J.K. Liao Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase Circulation 106 2002 57 62
148. N. Takizawa, Y. Koga, and M. Ikebe Phosphorylation of CPI17 and myosin binding subunit of type 1 protein phosphatase by p21-activated kinase Biochem Biophys Res Commun 297 2002 773 778
149. M.C. Tamby, Y. Chanseaud, M. Humbert, J. Fermanian, P. Guilpain, and P. Garcia-de-la-Peña-Lefebvre Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension Thorax 60 2005 765 772
150. S. Tawara, Y. Fukumoto, and H. Shimokawa Effects of combined therapy with a Rho-kinase inhibitor and prostacyclin on monocrotaline-induced pulmonary hypertension in rats J Cardiovasc Pharmacol 50 2007 195 200
151. Y. Toshima, S. Satoh, I. Ikegaki, and T. Asano A new model of cerebral microthrombosis in rats and the neuroprotective effect of a Rho-kinase inhibitor Stroke 31 2000 2245 2250
152. R.C. Trembath, J.R. Thomson, R.D. Machado, N.V. Morgan, C. Atkinson, and I. Winship Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia N Engl J Med 345 2001 325 334
153. R.M. Tuder, S.H. Abman, T. Braun, F. Capron, T. Stevens, and P.A. Thistlethwaite Development and pathology of pulmonary hypertension J Am Coll Cardiol 54 1 Suppl. 2009 S3 S9
154. R.M. Tuder, C.D. Cool, M.W. Geraci, J. Wang, S.H. Abman, and L. Wright Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension Am J Respir Crit Care Med 159 1999 1925 1932
155. R.M. Tuder, B. Groves, D.B. Badesch, and N.F. Voelkel Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension Am J Pathol 144 1994 275 285
156. R.M. Tuder, and N.F. Voelkel Pulmonary hypertension and inflammation J Lab Clin Med 132 1998 16 24
157. R.M. Tuder, and A.L. Zaiman Pathology of pulmonary vascular disease A. Peacock, L.J. Rubin, Pulmonary circulation 2nd ed. 2004 Arnold London 25 32
158. M. Uehata, T. Ishizaki, H. Satoh, T. Ono, T. Kawahara, and T. Morishita Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension Nature 389 1997 990 994
159. E. VanBavel, O. Sorop, D. Andreasen, M. Pfaffendorf, and B.L. Jensen Role of T-type calcium channels in myogenic tone of skeletal muscle resistance arteries Am J Physiol Heart Circ Physiol 283 2002 H2239 H2243
160. R.R. Vanderpool, A.R. Kim, R. Molthen, and N.C. Chesler Effects of acute Rho kinase inhibition on chronic hypoxia-induced changes in proximal and distal pulmonary arterial structure and function J Appl Physiol 110 2011 188 198
161. G. Velasco, C. Armstrong, N. Morrice, S. Frame, and P. Cohen Phosphorylation of the regulatory subunit of smooth muscle protein phosphatase 1M at Thr850 induces its dissociation from myosin FEBS Lett 527 2002 101 104
162. N.F. Voelkel, C. Cool, S.D. Lee, L. Wright, M.W. Geraci, and R.M. Tuder Primary pulmonary hypertension between inflammation and cancer Chest 114 3 Suppl. 1998 225S 230S
163. C.A. Wagenvoort, and N. Wagenvoort Primary pulmonary hypertension a pathologic study of the lung vessels in 156 clinically diagnosed cases Circulation 42 1970 1163 1184
164. Y. Ward, S.F. Yap, V. Ravichandran, F. Matsumura, M. Ito, and B. Spinelli The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway J Cell Biol 157 2002 291 302
165. A. Wibberley, Z. Chen, E. Hu, J.P. Hieble, and T.D. Westfall Expression and functional role of Rho-kinase in rat urinary bladder smooth muscle Br J Pharmacol 138 2003 757 766
166. D.W. Wilson, H.J. Segall, L.C. Pan, and S.K. Dunston Progressive inflammatory and structural changes in the pulmonary vasculature of monocrotaline-treated rats Microvasc Res 38 1989 57 80
167. D.P. Wilson, M. Susnjar, E. Kiss, C. Sutherland, and M.P. Walsh Thromboxane A2-induced contraction of rat caudal arterial smooth muscle involves activation of Ca2+ entry and Ca2+ sensitization: Rho-associated kinase-mediated phosphorylation of MYPT1 at Thr-855, but not Thr-697 Biochem J 389 2005 763 774
168. D.P. Wilson, C. Sutherland, and M.P. Walsh Ca2+ activation of smooth muscle contraction: evidence for the involvement of calmodulin that is bound to the triton insoluble fraction even in the absence of Ca2+ J Biol Chem 277 2002 2186 2192
169. S. Wolfrum, A. Dendorfer, Y. Rikitake, T.J. Stalker, Y. Gong, and R. Scalia Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection Arterioscler Thromb Vasc Biol 24 2004 1842 1847
170. E.Z. Xu, C. Kantores, J. Ivanovska, D. Engelberts, B.P. Kavanagh, and P.J. McNamara Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension Am J Physiol Heart Circ Physiol 299 2010 H1854 H1864
171. T. Yamakawa, S. Tanaka, K. Numaguchi, Y. Yamakawa, E.D. Motley, and S. Ichihara Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells Hypertension 35 2000 313 318
172. E.S. Yi, H. Kim, H. Ahn, J. Strother, T. Morris, and E. Masliah Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study Am J Respir Crit Care Med 162 2000 1577 1586
173. J.X. Yuan, A.M. Aldinger, M. Juhaszova, J. Wang, J.V. Conte Jr., and S.P. Gaine Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension Circulation 98 1998 1400 1406
174. J.X.J. Yuan, and L.J. Rubin Pathogenesis of pulmonary arterial hypertension: the need for multiple hits Circulation 111 2005 534 538
175. P. Zhu, L. Huang, X. Ge, F. Yan, R. Wu, and Q. Ao Transdifferentiation of pulmonary arteriolar endothelial cells into smooth muscle-like cells regulated by myocardin involved in hypoxia-induced pulmonary vascular remodelling Int J Exp Pathol 87 2006 463 474
176. A.J.A. Ziino, J. Ivanovska, R. Belcastro, C. Kantores, E.Z. Xu, and M. Lau Effects of rho-kinase inhibition on pulmonary hypertension, lung growth, and structure in neonatal rats chronically exposed to hypoxia Pediatr Res 67 2010 177 182
177. B.S. Zuckerbraun, D.A. Stoyanovsky, R. Sengupta, R.A. Shapiro, B.A. Ozanich, and J. Rao Nitric oxide-induced inhibition of smooth muscle cell proliferation involves S-nitrosation and inactivation of RhoA Am J Physiol Cell Physiol 292 2007 C824 C831